1. INTRODUCTION
1.5. Non-classical lignans - furoindane stilbenolignans (FIS)
Furoindane stilbenolignans (FIS) are a little-known group of hybrid polyphenols produced by land plants, structurally related to furofuran lignans like 9g (chapter 1.2, figure 3) and stilbene dimers like 50 (chapter 1.4.3). They are presumably formed by mixed oxidative coupling of two persistent phenoxyl radicals, one formed by oxidation a monolignol, the other by similar oxidation of a stilbene (see above, scheme 17).97 All known FISs therefore trace their origin to either coniferyl alcohol (8b) or sinapyl alcohol (8c) and to stilbenes resveratrol (5), isorhapontigenin (7) and piceatannol (6) (chapter 1.1, figure 2). The exact mechanism of their biosynthesis is unknown, but it is assumed to be similar to the biosynthesis of 8-8’ lignans (e.g. furofuranes 9g) and indanoindane stilbene dimers like 50. At the time of writing, six members of this group have been isolated (figure 9).
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Figure 9. Structures of all known FISs as reported in the original isolation reports. Type-I:
gnetifolin F (I), lehmbachol D (II), kompasinol A (III), 11-deoxykompasinol A (IV), 13-
hydroxykompasinol A (V), kompasinol P (VI); Type-II: cararosin A (IIIb); the originally proposed structure of rel-(7S,8R,7’R,8’S)-gnetifolin F (Ib).
Gnetifolin F (I) was isolated in racemic form from four different species of the genus Gnetum and from Pouzolzia sanguinea,97-101 Racemic lehmbachol D (II) was obtained from Gnetum cleistostachyum,97 while optically active sample of (+)-II was obtained from Salacia lehmbachii.102 First isolated from Maackia amurensis and therefore originally named maackoline,103 kompasinol A (III) was subsequently isolated under the new name from the genera Maackia, Kompassia, Caragana, Syagrus and Smilax.104-109 In all cases, III was obtained in racemic form. Optically active (–)-11- deoxykompasinol A (IV) was isolated from Orychophragmus violaceus.110 Racemic 13-hydroxy kompasinol A (V) was found together with III in Syagrus romanzoffiana.106 The last congener to be discovered so far is racemic kompasinol P (VI) from Caragana stenophylla.109 All FISs mentioned so far, that is compounds I-VI, share the same relative configuration rel-(7S,8R,7’R,8’S), for the purposes of this discussion termed type-I.
In contrast to that, cararosin A (IIIb), isolated from two members of the genus Caragana
111,112 was assigned rel-(7R,8R,7’R,8’R), here referred to as type-II. However, comparison of its NMR spectra recorded in DMSO-d6 111 with the spectra of kompasinol A (III) taken in methanol-d4 and acetone-d6 103,104,106,107 strongly suggest that III3b and III are an identical compound. Similarly, when first isolated, gnetifolin F (I) was assigned as rel-(7R,8R,7’R,8’R), type II (Ib),98,100 based on NOE difference spectrum obtained from the more soluble pentaacetate of Ib. The characteristic interaction used were H-7/ H-8 and H-7’/H-8’. Authors of this study also obtained single crystal X-ray data on Ib, which contradict their conclusions about relative configuration, however for unknown reasons did not resolve the discrepancy. Later, based on the NOE study of the free phenol, the relative configuration was reassigned as rel-(7S,8R,7’R,8’S), type-I.99 The identity of the original sample of Ib, studied as its pentaacetate, and later obtained samples of I from other plants have not been proven.
It should be noted that in cyclopentanes, 1H-1H coupling constants as well as through-space interactions are sometimes difficult to predict and interpret. In structure type-I, NOE interaction between 7-H(α) and 8-H(β) and between 7’-H(β) and 8’-H(α) are seen even though the respective
23 hydrogens are trans-oriented, therefore interaction between 7-H and 6’-H should be used instead.113 Based on these considerations it seems likely, that all natural FISs share type-I configuration. All isolation reports including available data regarding relative configuration and optical activity of FIS are summarized in table 1.
Table 1. Isolated natural furoindane stilbenolignans reported up to 2022, in chronological order.
Year Compound Ref. Isolated from Family a) [α]D (solvent) 1991 I 98 Gnetum parvifolium Gnetaceae II b),c) 0
1995 III 103 Maackia amurensis Fabaceae I, b) 0 1996 III 113 Koompassia malaccensis Fabaceae I b) 0 d)
1997 II 102 Salacia lehmbachii Celastraceae n.d. +25.1 (MeOH) 2003 IIIb 111 Caragana rosea Fabaceae II b) –3.7 (acetone)
2003 I 99 Gnetum klossi Gnetaceae I b) 0 (MeOH)
2005 III 105 Caragana tibetica Fabaceae I n.d.
2006 I 97 Gnetum cleistostachyum Gnetaceae I n.d.
2006 II 97 Gnetum cleistostachyum Gnetaceae I b) n.d.
2008 III 106 Syagrus romanzoffiana Arecaceae I b) 0 2008 V 106 Syagrus romanzoffiana Arecaceae I b) 0 e)
2013 III 107 Smilax glabra Smilacaceae I n.d.
2017 IIIb 112 Caragana changduensis Fabaceae n.d. n.d.
2019 I 100 Gnetum latifolium Gnetaceae II n.d.
2020 I 101 Pouzolzia sanguinea Urticaceae I n.d.
2021 III 108 Caragana stenophylla Fabaceae I n.d.
2021 III 109 Caragana stenophylla Fabaceae I +4.0 (MeOH) d) 2021 VI 109 Caragana stenophylla Fabaceae I b) +5.0 (MeOH) d) 2022 IV 110 Orychophragmus violaceus Brassicaceae I b) –58.6 (MeOH) e)
a) Relative configuration (type-I: rel-(7S,8R,7’R,8’S), type-II: rel-(7R,8R,7’R,8’R)). b) Assigned by NOE. c) X-ray structure available. d) Assessed racemic by HPLC. e) Optical activity/inactivity confirmed by CD.
FISs are widely distributed, spanning 7 families of seed-bearing plants (spermatophytes) including both gymnosperms and angiosperms. These are Gnetaceae (tropical trees and lianas);
Fabaceae (legumes); Celastraceae (tropical vines and shrubs); Arecaceae (commonly palms);
Smilacaceae (tropical and subtropical herbs and wines); Urticaceae (nettles); and Brassicaceae (crucifers). This wide distribution, combined with their mostly racemic form, suggests that some FISs may be formed nonenzymatically by coupling of free radicals derived oxidatively from stilbenes and monolignols.95,96 This may occur either in the living or dead cells of stilbene-producing plants, or as an artefact of extraction, purification and storage of plant materials.114 Inorganic oxidants, potentially including molecular oxygen in the presence of transition metal ions (Fe, Cu), may be responsible for nonselective coupling of phenols (chapter 1.4.3, scheme 17).97
In contrast to that, lehmbachod D (II) 102 and 11-deoxykompasinol A (IV) 110 were found to be optically active, with values of [α]D +25.1 (c 0.86, MeOH) and –58.6 (c 0.1, MeOH), respectively.
This was further corroborated by comparison of their experimental and calculated ECD spectra. This strongly suggests that their biosynthesis involves yet undiscovered enzymes or dirigent proteins
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(chapter, 1.4.2).84 It remains however unclear whether the found specific rotation values for both natural products represent those of individual single enantiomers or those of an enriched mixture of both enantiomers. HPLC separation of the enantiomers from racemic natural kompasinol A (III) 109 provided samples with significantly higher values of [α]D +103.6 and –135.5 (c 0.1, MeOH).
1.5.1. Biological activity of FIS
Due to the limited availability of natural FIS, only little bioactivity data have been reported (table 2). Besides antioxidant activity 105 that is common in natural and synthetic polyphenols, anti- inflammatory activity has been reported for I and III 97,100,108 and antidiabetic activity via inhibition of α-glucosidase type IV for III and V.106
Table 2. Reported biological activities of FIS.
Compound Activity
I 97 Anti-inflammatory: moderate inhibition of TNF-α production by murine peritoneal macrophages, IC50 = 9.2 µM.
I 100 Anti-inflammatory: neuroinflammation reduction, suppresses the upregulation of NO release by Aβ1-42 (amyloid beta1-42) transfection in BV2- cells (microglial cells).
I 101 Cytotoxicity vs. CAL27: 73.0 ± 1.0% viability at 30 µM, human oral adenosquamous carcinoma cells. Weak activity.
I 101 Cytotoxicity vs. MDA-MB-231: 78.8 ± 0.9% viability at 30 µM, human breast cancer cells. Weak activity.
II 97 Anti-inflammatory: moderate inhibition of TNF-α production by murine peritoneal macrophages, IC50 = 11.0 µM.
III 105 Antioxidant activity: in vitro superoxide anion scavenging.
III 108 Anti-inflammatory: rheumatoid arthritis, inhibition of NO production in
lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells, IC50 = 68.54 ± 0.68 µM (N-nitro-L-arginine methyl ester hydrochloride pos. control 41.13±2.35 μM).
III 109 No cytotoxicity: against RAW 264.7 cells.
III 106 Antidiabetic: α-glucosidase type IV inhibition IC50 = 11.2 µM (acarbose control 40 nM), reduction of postprandial blood glucose level by 10.2% at 10 mg/kg in Wistar rats (sucrose challenge).
IIIb 111 No anti-HIV activity in vitro.
IV 110 Cytotoxicity vs. Hela: IC50 = 9.43±0.62 µM (Cisplatin pos. control 11.53±1.07 µM), human cervical cancer cell.
IV 110 Cytotoxicity vs. HepG2: IC50 = 18.23±1.31 µM (Cisplatin pos. control 14.81±0.92 µM), human liver cancer cell.
V 106 Antidiabetic: α-glucosidase type IV inhibition IC50 = 6.5 µM (acarbose control 40 nM).
VI 109 No anti-inflammatory: activity: inhibition of NO production in LPS-stimulated RAW 264.7 cells. No cytotoxicity against RAW 264.7 cells.
25 Compounds I and IV were found to be cytotoxic.101,110 This fact is not surprising, because FISs are derived from natural oxygenated stilbenes and resemble to some degree the highly cytotoxic alkaloid colchicine (57) and stilbenoid combretastatins (figuree 10).5,115,116 The fixed dihedral angle between the B and C rings in on the FIS core mimics the three-dimensional structure of the antitumor cis-stilbene combretastatin A4 as well as many synthetic colchicine-binding site inhibitors.117
Figure 10. Comparison of the structure of lehmbachol D (II) with cytotoxic combretastatin A4 and colchicine (57).